<b><i>Introduction:</i></b> The objective was to evaluate: (i) the proportion of prenatally diagnosed congenital heart disease (CHD) associated with an abnormal quantitative fluorescence-PCR (QF-PCR), chromosome microarray (CMA), and exome sequencing (ES) result; and (ii) the diagnostic yield of these technologies based on CHD category and presence of extra-cardiac anomalies (ECAs). <b><i>Methods:</i></b> This prospective cohort study was set across 12 UK foetal medicine centres. All cases underwent QF-PCR, CMA, and ES, and the diagnostic yield in <i>n</i> = 147 cases of prenatally diagnosed CHD was assessed. <b><i>Results:</i></b> In 34.7% (<i>n</i> = 51/147), a genetic diagnosis was obtained. Using a stepwise testing strategy, the diagnostic yield for QF-PCR, CMA, and ES was 15.6% (<i>n</i> = 23/147), 13.7% (<i>n</i> = 17/124), and 10.2% (<i>n</i> = 11/107), respectively. Abnormal QF-PCR/shunt (septal) defects 31.4% (<i>n</i> = 11/35), <i>p</i> = 0.046, and abnormal CMA/conotruncal anomalies 22.7% (<i>n</i> = 10/44), <i>p</i> = 0.04, had significant associations. Monogenic variants were commonest in complex CHD 36.4% (<i>n</i> = 4/11). Multisystem CHD had a greater diagnostic yield overall compared to isolated OR 2.41 (95% CI, 1.1–5.1), particularly in association with brain and gastrointestinal tract anomalies. The proportion of variants of uncertain significance was 4.7% (<i>n</i> = 5/107) with ES, with none in the CMA group. <b><i>Conclusion:</i></b> In the era of prenatal ES, there remains an important role for QF-PCR and CMA. Identification of monogenic pathologic variants further allows delineation of prognosis in CHD.

Prognosis is good when the facial dismorphysm is isolated and poor in association with chondrodysplasia punctata, with a high risk of mortality by 2 years of age.